Anti-Müllerian hormone and fertility assessment
It is estimated that around 1 in 6 couples have difficulty conceiving, with causes of infertility split equally between male and female factors. Although it is well known that a woman’s fertility declines sharply from the age of 35 onwards, it is perhaps less discussed that infertility also affects women in younger age groups (7% of 20–24-year-olds; 9% of 25–29-year-olds and 15% of 30–34-year-olds). As June was World Infertility Awareness Month, CLI caught up with Heather Read-Harper, Senior European Marketing Manager for Immunoassay and Clinical Chemistry of Beckman Coulter, to find out more about anti- Müllerian hormone, what it is an indicator of and how testing for it can help with assessing some of the possible causes of female infertility and therefore informing the development of individually tailored treatment options.
What is anti-Müllerian hormone (AMH) and what is its normal role?
Anti-Müllerian hormone (AMH) also known as Müllerian inhibiting substance (MIS) is a glycoprotein that belongs to the transforming growth factor beta family. It was first discovered in 1947 by Alfred Jost. His discovery led to the understanding that AMH regulates sex differentiation in the embryo/fetus. In males, AMH is secreted by the Sertoli cells of the testis. During embryonic development, AMH is responsible for Müllerian duct regression. AMH continues to be produced by the testicles until puberty and then decreases slowly to residual post-puberty values. In females, AMH is produced in small amounts by ovarian granulosa cells after birth until menopause, and then becomes undetectable . This is demonstrated well in Figure 3 in Jopling et al. https://onlinelibrary.wiley.com/doi/full/10.1002/edm2.21# 
How does it relate to fertility in females?
AMH concentrations in adult women reflect the number of small follicles entering the growth phase of their life cycle, which reflects the number of primordial follicles that remain in the ovary, known as the ovarian reserve.
AMH is produced by the granulosa cells of the preantral and small antral ovarian follicle up until the time of menopause. It regulates follicle recruitment by decreasing the sensitivity of small antral follicles to follicle-stimulating hormone (FSH) activity (Fig. 1) .
AMH has become widely used to evaluate ovarian status because of the direct association to the developing follicles and its potential to be measured on any day in the menstrual cycle as compared to FSH, which is an indirect measure of the ovarian status and must be measured on specific days of the cycle.
What are some examples of the challenges to fertility in women?
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females of reproductive age. It is a condition where the ovaries may develop numerous small follicles and may result in failure to ovulate. The level of AMH can be two- to four-fold higher in women with PCOS.
At various ages, women can exhibit a wide range of AMH levels. These levels can be used to predict the onset of menopause . A woman with a high level of AMH will go through menopause later than one who has a low level of AMH. Fertility declines between 10 and 15 years prior to menopause; therefore, understanding a woman’s individual AMH levels can help guide fertility-related decisions. Premature menopause or primary ovarian insufficiency affects women under the age of 40 and is commonly the result of medical condition or treatment but may also be spontaneous, with no known cause. AMH can be used in the diagnosis of this condition.
One of the first clinical applications of AMH was as a tumour marker, used in the diagnosis and follow-up of adult women with ovarian granulosa cell tumours (AGCT). AMH is a sensitive and specific marker of AGCT and can be monitored during follow-up. Combining AMH and inhibin B in AGCT patient follow-up, however, improves the detection of recurrent disease .
How does AMH measurement help to diagnose and guide treatment for these conditions?
For over 20 years, clinicians have been using AMH to help guide patient care related to reproductive health. High-quality diagnostic assays have evolved over the past two decades and they continue to provide precise insight to support clinical decisions as to reproductive aging, fertility and pregnancy monitoring
Women with normal AMH values will tend to have a good response to ovarian stimulation and have more eggs retrieved. In general, having a higher number of eggs improves the success rate because clinicians are more likely to have at least one high-quality embryo available for transfer back to the uterus. Women with a high AMH level run the risk of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening condition . At the other extreme, women with a low AMH are not likely to respond well to in vitro fertilization (IVF) and can therefore be offered appropriate counselling or alternative treatment options.
AMH can be used to individualize a patient-care strategy for controlled ovarian stimulation (COS). Knowing these values can reveal which patients are unlikely to respond to IVF. We have determined that a cut-off AMH concentration of 6.64pmol/L (determined by Access AMH Advanced) may predict poor ovarian response as defined by retrieval of up to four oocytes in women undergoing COS. Women with AMH values above this cut-off have a high predictability of retrieving more than four oocytes during COS.
AMH assessment may also help physicians identify women at risk for hyperstimulation in COS by providing a cut-off AMH concentration of >12.64pmol/L (determined by Access AMH Advanced) which corresponds to an antral follicle count (AFC) value of greater than 15 oocytes retrieved, indicating high ovarian reserve. This helps physicians make better decisions early in their diagnostic process.
Many women now delay motherhood for many reasons and can then struggle with reduced fertility. How is AMH useful in this situation?
The mean age of women in the European Union on giving birth to their first child has gradually increased from 28.8 years in 2013 to 29.4 years in 2019 . In the UK, between 1991 and 2019 there has been a clear trend of mothers having children later in life, with the average age of mothers increasing from 27.7 in 1991 to 30.7 by 2019 .
Fertility begins to decline after the age of approximately 30, due to the reduction in the quality and quantity of follicles. A similar decline in the level of AMH is also evident (Fig. 2)  because AMH levels are positively associated with the AFC.
As a result, it is important to understand the impact of follicular aging if making the decision to delay starting a family. Although IVF is an option for older women, it is not always successful. Some women may have to undergo multiple rounds of IVF. In other cases, IVF may not be an option because a low ovarian reserve is already evident. In such situations, women may want to consider using donor eggs.
The current Covid-19 pandemic has interrupted diagnosis and treatment of many conditions, one common example being cancer. What has been the situation regarding infertility assessment and in vitro fertilization?
Early in the COVID-19 pandemic, the European Society of Human Reproduction and Embryology, identified the need to provide a recommendation on how to manage reproductive care. They concluded that reproductive treatment should be discontinued except for the most urgent cases .
Recently, with improvement in the control of the virus owing to test and trace and vaccine roll out, along with the analysis of additional data, the society has recommended a gradual recommencement of full reproductive treatment.
What do you envisage for the future development of infertility assessment and treatment?
Clinicians are focusing attention on the utility of AMH testing in assessing the long-term implications of therapy in terms of gonadal damage and related infertility in young cancer suffers. AMH is now being used to investigate which therapeutic regimens may be most toxic to the ovaries. This information helps guide the choice of treatment by offering a prediction (and potential preservation) of fertility in young women.
In the future, as women look to make more informed lifestyle decisions, AMH may play a role in longer term assessment of reproductive status. As new services, such as egg freezing and egg donation, become more readily available and women continue the trend to delay conception, AMH will be a vital tool in associated assessments.
Heather Read-Harper BSc, Senior European Marketing Manager for Immunoassay and Clinical Chemistry Beckman Coulter United Kingdom Limited, High Wycombe, Buckinghamshire, UK
To read about AMH assays, please visit Beckman Coulter (https://www.beckmancoulter.com/products/ immunoassay/access-amh)